Bibliographic details of the publications referred to by author in this specification are collected alphabetically at the end of the description.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.
The details concerning the biological mechanisms underlying the development and progression of a number of diseases and disorders affecting the central nervous system including neuro-psychotic diseases, such as schizophrenia; neuro-degenerative diseases, such as Parkinson's disease; as well as addictions, such as alcohol or opiate dependency, remain unclear. Collectively, they are disabling and emotionally devastating illnesses, and options for treatment for a number of these diseases and disorders remains inadequate.
Schizophrenia, for example, is a severe mental illness which affects approximately one person in a hundred. The symptoms that are most commonly associated with the disease are called positive symptoms, that denote the presence of grossly abnormal behaviour. These include thought disorder (speech which is difficult to follow or jumping from one subject to another with no logical connection), delusions (false beliefs of persecution, guilt, grandeur or being under outside control) and hallucinations (visual or auditory). Thought disorder is the diminished ability to think clearly and logically. Often it is manifested by disconnected and nonsensical language that renders the person with schizophrenia incapable of participating in conversation, contributing to alienation from family, friends and society. Delusions are common among individuals with schizophrenia. An affected person may believe that they are being conspired against (called “paranoid delusion”). “Broadcasting” describes a type of delusion in which individuals with this illness believe that their thoughts can be heard by others. Hallucinations can be heard, seen or even felt. Most often they take the form of voices heard only by the afflicted person. Such voices may describe the person's actions, warn of danger or instruct what to do. At times the individual may hear several voices carrying on a conversation. Less obvious than the above “positive symptoms” and “thought disorder” but equally serious are the deficit or negative symptoms that represent the absence of normal behaviour. These include flat or blunted affect (i.e. lack of emotional expression), apathy, social withdrawal and lack of insight.
The onset of schizophrenia usually occurs during adolescence or early adulthood, although it has been known to develop in older people. Onset may be rapid with acute symptoms developing over several weeks, or it may be slow developing over months or even years. Schizophrenia is, in fact, a fairly common disorder. It affects both sexes equally and strikes about 1% of the population worldwide. Another 2-3% have schizotypal personality disorder, a milder form of the disease.
Like a number of other neuro-degenerative and neuro-psychotic disorders, the causes of schizophrenia are not fully understood. However, during the last few years there has emerged a body of literature which supports an abnormality in oxidation homeostasis systemically and centrally in schizophrenia. The origin of this oxidative stress is still unknown. The brain in schizophrenia exhibits many chemical hallmarks of oxidative attack, in addition to indications of altered antioxidant defence. Any tissue under sustained radical attack may suffer a depletion of the key free radical/H2O2 scavenger in the brain, glutathione. Recently, reports have emerged that glutathione is indeed depleted in schizophrenia, and that the antioxidant enzymic activities related to glutathione metabolism are markedly perturbed. Do K Q, Trabesinger A H, Kirsten-Kruger M, Lauer C J, Dydak U, Hell D, Holsboer F, Boesiger P and Cuenod M., (2000), Euro J Neurosci, 12:3721-8 have reported a significant decrease (−27%) in the cerebrospinal fluid levels of glutathione in drug-free schizophrenia patients compared to controls. This decrease is consistent with the previously reported decrease in the levels of the glutathione metabolyte gamma-glutamylglutamine in the cerebrospinal fluid of such patients (Do K Q, Lauer C J, Schreiber W, Zollinger M, Gutteck-Amsler U, Cuenod M and Holsboer F., (1995), J Neurochem, 65:2652-62). Furthermore, Do et al., (2000) also found a 52% decrease in glutathione levels in the medial prefrontal cortex of schizophrenia patients compared to controls, using a non-invasive proton magnetic resonance spectroscopy method.
Intriguingly, other aspects of the glutathione metabolic pathway are also perturbed in schizophrenia. Decreased peripheral glutathione peroxidase (GPx) activity has been described in schizophrenia patients (Abdalla D S, Monteiro H P, Oliveira J A and Bechara E J., (1986), Clin Chem, 32:805-7), and the decrease correlates with increased brain atrophy (Buckman T D, Kling A S, Eiduson S, Sutphin M S and Steinberg A., (1987), Biol Psychiatry, 22:1349-56). Plasma GPx positively correlates with psychosis rating scored in schizophrenia patients on or off medication (Yao J K, Reddy R D and van Kammen D P., (1999), Biol Psychiatry, 45:1512-5). GPx is the enzyme that catalyses the scavenging of H2O2 and other radicals by glutathione.
These biochemical changes have led to a call for the critical study of antioxidants as schizophrenia treatments utilised adjunctively with antipsychotic medication. To date, research has focused on the use of indirect means of overcoming the defects in glutathione metabolism such as increasing the efficiency of other radical scavenging systems. For example, Vitamin C, Vitamin E (alpha-tocopherol), alpha-lipoic acid supplements and also selenomethionione have been investigated. Currently, investigators are focusing on the use of Vitamins E and C (Yao et ah, 1999, supra). Selenomethionione supplementation is well known to augment the activity of glutathione peroxidase (Duffield A J, Thomson C D, Hill K E and Williams S., (1999), Am J Clin Nutr, 70:896-903). Vitamin E and selenium combined supplementation has already been reported to provide beneficial effects in the treatment of the FALS transgenic mouse model (Gurney M E, Cutting F B, Zhai P, Doble A, Taylor C P, Andrus P K and Hall E D., (1996), Ann Neurol, 39:147-57), demonstrating that the potential antioxidant benefits of such oral supplementation can also be transduced across the blood brain barrier in brain oxidation disorders. However, while being supportive of glutathione metabolism, in that these molecules can function as antioxidants, they are not the most efficient means of increasing glutathione levels in the brain.
In addition to impaired antioxidant defence, abnormalities in neurotransmitters and neuroplasticity have also been identified in patients suffering from schizophrenia (Arnold et al., 2005). Some of the implicated neurotransmitters include dopamine, GABA and acetylcholine (Zheng et al., 2012). Additionally, release of the excitatory neurotransmitter, glutamate is thought to be overstimulated in schizophrenia, leading to activation of toxic intracellular pathways involving calcium (Reiter et al., 1995). Elevations to intracellular calcium and dysfunctional calcium signalling have thus been implicated in cognitive impairment in schizophrenia (Lidow, 2003) and are known triggers for apoptosis (Mattson & Chan, 2003).
Accordingly, there is an on-going need to develop methods of treating and/or preventing schizophrenia, either in the form of adjunctive therapies to currently utilised treatments or as a replacement to the use of currently available antipsychotic medication.
Mangosteen (Garcinia mangostana) is an evergreen tall tree which belongs to the Clusiaceae (Guttiferae) family Garcinia mangostana is related to other mangosteens, such as the button mangosteen (G. prainiana) or the charichuelo (G. madruno). It originated in South East Asia, and is today cultivated as a fruit tree throughout the region, including but not limited to Thailand, India, Sri Lanka, and Malaysia. A popular eating fruit, the flesh of the mangosteen is sweet and fibrous, and is surrounded by an inedible rind, or exocarp, when ripe. In each fruit, the edible segmented flesh surrounds a seed.
The mangosteen fruit pericarp and exocarp contain a number of bioactive compounds, including, but not limited to, polyphenols, such as xanthones and tannins, as well as anthocyanins, procyanins, prodelophinidins and associated stereoisomers, such as epi-catechins. The unique composition is astringent which discourages infestation by insects, fungi, plant viruses, bacteria and animal predation. Over 85 secondary metabolites have been isolated from the pericarp of mangosteen, which includes over 60 xanthones. Xanthones have been isolated from a number of plant sources, but are particularly common to the Bonnetiaceae and Clusiaceae families and in some species in the family Podostemaceae.
As stated above, mangosteen is a popular eating fruit throughout South East Asia. Various parts of the plant have also been used in traditional medicine as an anti-inflammatory, an antimicrobial or to treat skin infections, wounds, dysentery. However, work to date on the phytochemistry of the mangosteen plant and fruit has been inconclusive and insufficient to verify its safety or efficacy for use as a supplement or for medical treatment. The applicants of the present application have now surprising found that plant extracts, such as those derived from mangosteen pericarp, and the specific compounds they contain, offer an effective adjunct or replacement therapy for the treatment and/or prophylaxis of diseases or disorders of the central nervous system, including neuro-degenerative or neuro-psychotic disorders, such as schizophrenia.